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Profiles of circulating histidine-rich glycoprotein associate with chronological age and risk of all-cause mortality

By Mun-Gwan Hong, Tea Dodig-Crnkovic, Xu Chen, Kimi Drobin, Woojoo Lee, Yunzhang Wang, Fredrik Edfors, David Kotol, Cecilia Engel Thomas, Ronald Sjöberg, Jacob Odeberg, Anders Hamsten, Angela Silveira, Per Hall, Peter Nilsson, Yudi Pawitan, Sara Hagg, Mathias Uhlen, Nancy L. Pedersen, Patrik Magnusson, Jochen M Schwenk

Posted 09 Nov 2018
bioRxiv DOI: 10.1101/464909 (published DOI: 10.26508/lsa.202000817)

Despite recognizing aging as risk factor of human diseases, little is still known about the molecular traits of biological age and mortality risk. To identify age-associated proteins circulating human blood, we screened 156 subjects aged 50-92 years using an exploratory and multiplexed affinity proteomics approach. We corroborated the top age-associated protein profile (adjusted P < 0.001) in eight additional study sets (N = 4,044 individuals), and confirmed a consistent age-associated increase (P = 6.61 × 10-6) by meta-analysis. Applying antibody validation determined circulating histidine-rich glycoprotein (HRG) as the target, and we observed that sequence variants influenced the antibodies ability to bind to the protein. Profiles of circulating HRG were associated to several clinical traits and predicted the risk of mortality during a follow-up period of 8.5 years (IQR = 7.7-9.3 years) after blood sampling (HR = 1.25 per SD; 95% CI = 1.12-1.39; P = 7.41 × 10-5). In conclusion, our affinity proteomics analysis found associations between the molecular traits of circulating HRG with age and all-cause mortality. This suggests that the profiles of multi-purpose protein HRG could serve as an accessible indicator of physiological processes related to aging.

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